The hypoxia inducible factor (HIF) is a master regulator
of hypoxia inducible genes several of which facilitate
invasion and metastasis. Here, using our MR-compatible
cell perfusion assay, we investigated the effect of
HIF-1and
HIF-2silencing
on the ability of MDA-MB-231 breast cancer cells to
invade and degrade the extracellular matrix (ECM).
MDA-MB-231 HIF double knocked down cells showed a
significant decrease in invasion and ECM degradation, as
well as altered metabolism. These data demonstrate the
importance of silencing both HIF-1 and 2;
to reduce ECM degradation and invasion in this triple
negative aggressive and metastatic breast cancer cell
line.

The bioreactor techniques are becoming an important tool
to study cancer cell metabolism. Modeling of
intracellular MRS isotopomer data obtained during
perfusion with 13C labeled substrates allows
quantitative determination of transport and metabolic
parameters and fluxes in vivo/in situ. In this work we
develop a 13C metabolic “bonded cumomer” approach to fit
data obtained in bioreactor with 13C glucose perfusion
and elucidate cancer metabolism bionetwork.

Comparison of
Hyperpolarized [1-13C] Dehydroascorbate-MR and
FDG-PET in a Transgenic Prostate Cancer Model

Kayvan R. Keshari1, Victor Sai1,
Kristen Scott1, John Kurhanewicz1,
Henry F. VanBrocklin1, and David M. Wilson11Radiology and Biomedical Imaging, University
of California, San Francisco (UCSF), San Francisco, CA,
United States

We have developed a new in vivo redox sensor,
hyperpolarized [1-13C] dehydroascorbate (DHA), the
oxidized form of Vitamin C. This probe is rapidly taken
into the cell via glucose (GLUT) transporters and then
reduced to ascorbate (VitC), to a greater extent in
transgenic prostate (TRAMP) tumor than the normal gland.
Since [1-13C] DHA has an essentially identical transport
mechanism to 2-18F-2-deoxy-D-glucose (FDG), we
speculated the two techniques might have significant
overlap. DHA-MR and FDG-PET studies were performed in a
cohort of TRAMP mice at identical time points revealing
similar ability to distinguish between tumor and
surrounding benign tissue.

11:33

0060.

In VivoHyperpolarized13C-MRS
Shows Abnormal Cardiac Metabolism in the PPARKnockout
Mouse

Peroxisome proliferator-activated receptor-α (PPARα)plays
an important role in the regulation of fatty acid
oxidation. The PPARα knockout mouse (PPARα-KO) has been
developed to investigate the role of PPARα in cardiac
metabolism and disease. This work aimed to assess thein
vivometabolic
phenotype of PPARα-KO mice using hyperpolarized13C-MRS.
During the fed state, PPARα-KO mice had significantly
elevated pyruvate dehydrogenase (PDH) flux compared to
controls. During fasting there was a similar reduction
in PDH flux in both control and PPARα-KO mice,
indicating that this alteration is PPARα independent and
is a response to increased fatty acid supply and
utilization.

As part of the first hyperpolarized [1-13C]-pyruvate
clinical trial, we developed a specialized dynamic 13C
2D EPSI sequence using short multiband pulses, and
applied it in four prostate cancer patients.
Time-resolved MR spectroscopic imaging (MRSI) following
injection of hyperpolarized [1-13C]-pyruvate can provide
valuable and detailed metabolic information, including
perfusion, uptake and kinetics. We observed SNRs up to
340 for pyruvate within 15-20 sec after injection, and
SNRs up to 17 for lactate within 25-35 sec after
injection. The signal lasted for up to 75 sec for
pyruvate and 70 sec for lactate.

In this study, we hypothesized that the gradual IMCL
storage occurs in skeletal muscle during resting, and
such storage at resting state would alter in obesity.
Specifically, we investigated the IMCL storage at
resting state in obese rats by quantifying the rates of
IMCL accumulation using continuous and dynamic 1H-MRS.
We demonstrated that dynamic 1H-MRS could quantify the
IMCL accumulation at resting state in individual
muscles. Our preliminary results revealed that the
disorder of lipid metabolism in obesity is associated
with not only an increased IMCL content, but also the
alterations in the rates of IMCL storage at resting
state in both slow-oxidative muscle and fast-oxidative
glycolytic muscles.

Biophysical properties of intramyocellular lipid (IMCL)
such as droplet size may reflect the balance between
droplet synthesis and degradation. In this study, we
hypothesized that characterizing the restricted
diffusion of IMCL protons could serve as a sensitive
marker for monitoring IMCL droplet dynamics during
metabolic intervention/abnormality. Our experimental
results demonstrated that in vivo IMCL diffusion
characteristics are sensitive to metabolic manipulation
by fasting. During the 60-hr fasting, IMCL level
increased but exhibited more restricted diffusion,
largely in agreement with our histological observation
of more droplets but of smaller sizes. Such IMCL
diffusion characterization may serve as a sensitive
marker to probe the IMCL droplet dynamics in vivo.

In the present study, we used CD73-deficient mice to
characterize the metabolic consequences of impaired
extracellular adenosine formation using1H
MRI and1H/13C MRS for analysis of
body fat content and composition as well as hepatic and
myocellular lipid distribution. We found that disrupted
extracellular adenosine formation due to lack of CD73
leads to an enhanced lipolysis accompanied by
accumulation of intramyocellular lipids in skeletal
muscle and peripheral insulin resistance. These findings
suggest that CD73-derived adenosine is an important
modulator of lipolysis and might be critically involved
in development of diseases like diabetes mellitus and
the metabolic syndrome.

The exact role of pancreatic fat in the development of
human impaired glucose tolerance remains unclear. Basic
research using rodent models of type 2 diabetes has
identified pancreatic steatosis and lipotoxicity as a
leading cause of beta cell dysfunction. We sought to
translate these mechanistic studies into the clinical
population. Our data suggest that pancreatic steatosis
may identify a subset of asymptomatic individuals who
are at high risk for development of type 2 diabetes.
1H-MRS and measurement of pancreatic TG content may
constitute a new therapeutic target. Our data also
highlight a potential need for ethnically appropriate
preclinical biomarkers.